作者
Christine Wolf,Ee Lyn Lim,Mohammad Reza Mokhtari,Barbara Kind,Alexandru Odainic,Eusebia Lara-Villacanas,Sarah Koss,Simon Mages,Katharina Menzel,Katharina Engel,Gregor Dückers,Benedikt Bernbeck,Dominik T. Schneider,Kathrin Siepermann,Tim Niehues,Carl Christoph Goetzke,Pawel Durek,Kirsten Minden,Thomas Dörner,Anna Barbara Stittrich,Franziska Szelinski,Gabriela Maria Guerra,Mona Massoud,Markus Bieringer,Carina C. de Oliveira Mann,Eduardo Beltrán,Tilmann Kallinich,Mir‐Farzin Mashreghi,Susanne V. Schmidt,Eicke Latz,Johanna Klughammer,Olivia Majer,Min Ae Lee‐Kirsch
摘要
UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLR) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G, R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role of UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.